Hemostasis is achieved by blood vessel, platelets and blood coagulation factors that function normally. Reduced function of any of these elements enhances bleeding and extraordinary functional reduction induces excess bleeding to such an extent that life is even threatened.
Platelets, present in blood at 130,000 to 360,000/μL, promptly cluster around wounded portions of blood vessel to play an important role in hemostasis. When hemostatic function of platelets does not work normally or the number of circulating platelets is reduced (less than 50,000/μL) by some causes, bleeding is enhanced. In severe cases (less than 10,000/μL), bleeding is induced even spontaneously and thereby excess bleeding might threaten life. Thrombocytopenia caused by anti-cancer chemotherapy, which goes on increasing in recent years, is serious side effect. How to control bleeding disorders caused by thrombocytopenia is an important problem in treating cancer (J. Nishimura, Progress of Medicine 184: 448–452, 1998).
Principally, thrombocytopenia is divided into four classes in view of mechanism. The first class is caused by decrease in platelet production in bone marrow, including aplastic anemia, hematopoietic suppression in bone marrow after administration of anti-cancer agents, and alteration for normal hematopoietic organ as in acute leukemia. The second class is due to promotion of platelet destruction by anti-platelet antibody, including idiopathic thrombocytopenic purpura (ITP). This class also includes thrombocytopenia induced by drug allergy and newborn thrombocytopenia caused by unfit platelet blood type pregnancy. The third class is caused by accelerated consumption of platelets including disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP) wherein a large number of platelets is consumed at peripheral thrombopoietic sites to induce thrombocytopenia. Finally, the fourth class is due to abnormal distribution of platelets. In normal adults, platelets newly produced in bone marrow are peripherally released but about one third thereof is captured at the spleen without peripheral circulation. In case of hepatocirrhosis or splenomegalia, however, most of newly produced platelets are captured at the spleen. Consequently, in spite of platelet production in bone marrow, platelets are not sufficiently provided to peripheral circulation to thereby induce thrombocytopenia (Y. Kurata, Sogo Rinsho 47: 2742–2748, 1998). For platelet dysfunctions, thrombasthenia caused by deficiency of platelet membrane glycoproteins (GP) IIb/IIIa and Bernard-Soulier's syndrome caused by deficiency of GP Ib are known.
Hemostatic disorders caused by platelet disorders cause enhanced bleeding as shown by mucosal hemorrhage in a nose-mouse area and the gastrointestinal tract as well as exudation from wound, ulcer or injected site. Bleeding in thrombocytopenia is extensive and hence thrombocytopenia is a serious problem both during and after surgical operation. When the number of platelets is reduced as low as 50,000/μL or less, serious bleeding is likely to occur even in a minute surgical operation such as a tooth extraction. Further reduction in the number of platelets to as low as 10,000/μL or less might induce spontaneous bleeding in the absence of specific events such as surgical operation or trauma wherein intracranial hemorrhage might often be lethal.
Currently, transfusion of platelet concentrates is only clinically efficacious treatment for bleeding caused by thrombocytopenia or platelet dysfunction. In practice, platelet concentrates is basically administered so that there may be attained 50,000/μL or more of platelets in case of surgical operation or active bleeding or 20,000/μL or more of platelets in other cases (Ministry of Health and Welfare, Pharmaceutical Affairs Bureau; the Japanese Red Cross Society: As to proper use of platelet preparations).
However, when the platelet concentrates are administered frequently in a large amount, platelets derived from multiple blood donors are used. As a consequence, many patients who repeatedly received platelet transfusion will come to produce an isoantibody to HLA antigens of contaminated leukocytes, platelet blood-type antigens of platelets or membrane proteins of platelets and become incapable of platelet transfusion due to attenuated effects of transfusion. Moreover, possibility is not utterly denied that the platelet concentrates are contaminated with lymphocytes causative of post-transfusion GVHD or viruses that cause hepatitis or AIDS. Besides, shortage of supply is likely to occur since the platelet concentrates can effectively be used for as short as 3 to 5 days. Accordingly, there is an earnest desire for a medicament that is safe, easy to manage hemostasis and capable of storage, in place of platelet transfusion that is currently the only treatment for bleeding disorders caused by thrombocytopenia or platelet dysfunction.